title: NCoR1 regulates thyroid hormone receptor isoform-dependent adipogenesis.
abstract: We previously showed that two thyroid hormone receptor (TR) isoforms--TRα1 and TRβ1--differentially regulate thyroid hormone (triiodothyroxine, T(3))-stimulated adipogenesis in vivo. This study aims to understand the role of the nuclear receptor corepressor, NCoR1, in TR isoform-dependent adipogenesis. We found that T(3)-stimulated adipogenesis of 3T3-L1 cells was accompanied by progressive loss of NCoR1 protein levels. In 3T3-L1 cells stably expressing a mutated TRα1, PV (L1-α1PV cells), the T(3)-stimulated adipogenesis was more strongly inhibited than that in 3T3-L1 cells stably expressing an identical mutation in TRβ1 (L1-β1PV cells). The stronger inhibition of adipogenesis in L1-α1PV cells was associated with a higher NCoR1 protein level. These results indicate that the degree of loss of NCoR1 correlates with the extent of adipogenesis. siRNA knockdown of NCoR1 promoted adipogenesis of control 3T3-L1 cells and reversed the inhibited adipogenesis of L1-α1PV and L1-β1PV cells, indicating that NCoR1 plays an essential role in TR isoform-dependent adipogenesis. An ubiquitin ligase, mSiah2, that targets NCoR1 for proteasome degradation was upregulated on day 1 before the onset of progressive loss of NCoR1. NCoR1 was found to associate with mSiah2 and with TR, TRα1PV, or TRβ1PV, but a stronger interaction of NCoR1 with TRα1PV than with TRβ1PV was detected. Furthermore, TRα1PV-NCoR1 complex was more avidly recruited than TRβ1PV-NCoR1 to the promoter of the C/ebpα gene, leading to more inhibition in its expression. These results indicate that differential interaction of NCoR1 with TR isoforms accounted for the TR isoform-dependent regulation of adipogenesis and that aberrant interaction of NCoR1 with TR could underlie the pathogenesis of lipid disorders in hypothyroidism.
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Center for Cancer Research, 37 Convent Drive, Room 5128, Bethesda, Marryland 20892-4264, USA.
authors.forename: Xu-Guang
authors.initials: XG
authors.lastname: Zhu
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Michael L
authors.initials: ML
authors.lastname: Goodson
authors.forename: Martin L
authors.initials: ML
authors.lastname: Privalsky
authors.forename: Sheue-Yann
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000502:physiology*; D050156:Adipogenesis / Q000502:physiology*; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D006801:Humans; D051379:Mice; D009154:Mutation; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D015533:Transcriptional Activation; D014284:Triiodothyronine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D056971:Nuclear Receptor Co-Repressor 1; D047495:PPAR gamma; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; C533102:Siah2 protein, mouse; D044767:Ubiquitin-Protein Ligases